This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Early host-virus interactions that result in a prompt and robust decline of peak primary infection favor protection from HIV-1 and SIV disease progression. Increased turnover rates of CD4+ and CD8+ T cells in both SIV and HIV-1 infection parallel virus load and decrease following effective antiretroviral therapy (ART). Thus, a sustained virus load, directly or indirectly, promotes elevated T cell proliferation and generation of new susceptible target cells. Both non-antigen-specific homeostatic mechanisms responding to T cell destruction and antigen-specific proliferation have been suggested as mechanisms for increased T cell turnover. Recently, it has been shown that SIV selectively targets and destroys activated CD4+ memory T cells, particularly in mucosal tissues. Given the importance of CD4+ T cells in the evolution of appropriate CD8+ T cell and B cell responses and as an anti-viral effector cell, understanding the role of the CD4+ T cell as a target for virus replication and the relationship between viremia, enhanced T cell turnover and immune dysregulation are essential for the design of effective interventions. In this pilot project we will use T cell depletion and re-infusion of labeled T cells in the SIV macaque model to determine 1) the effect target cell pool size has on the magnitude of initial virus burst and on virus set point and 2) the phenotype, antigen specificity, turnover rates and trafficking patterns of lymphocyte subpopulations during primary infection and after control of viremia with ART. To accomplish these objectives, a chronic thoracic duct canulation model is being developed in rhesus macaques to 1) determine the effect of reducing the CD4+ T cell memory target cell pool on the kinetics of SIVmac239 replication during primary and set-point phases of infection, and its impact on anti-viral immunity and T cell homeostasis and 2) characterize lymphocyte turnover and trafficking in normal and in SIVmac239-infected macaques with and without ART.